ROS-responsive liposomes as an inhaled drug delivery nanoplatform for idiopathic pulmonary fibrosis treatment via Nrf2 signaling.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease with pathophysiological characteristics of transforming growth factor-ß (TGF-ß), and reactive oxygen species (ROS)-induced excessive fibroblast-to-myofibroblast transition and extracellular matrix deposition. Macrophages are closely involved in the development of fibrosis. Nuclear factor erythroid 2 related factor 2 (Nrf2) is a key molecule regulating ROS and TGF-ß expression. Therefore, Nrf2 signaling modulation might be a promising therapy for fibrosis. The inhalation-based drug delivery can reduce systemic side effects and improve therapeutic effects, and is currently receiving increasing attention, but direct inhaled drugs are easily cleared and difficult to exert their efficacy. Therefore, we aimed to design a ROS-responsive liposome for the Nrf2 agonist dimethyl fumarate (DMF) delivery in the fibrotic lung. Moreover, we explored its therapeutic effect on pulmonary fibrosis and macrophage activation. RESULTS: We synthesized DMF-loaded ROS-responsive DSPE-TK-PEG@DMF liposomes (DTP@DMF NPs). DTP@DMF NPs had suitable size and negative zeta potential and excellent capability to rapidly release DMF in a high-ROS environment. We found that macrophage accumulation and polarization were closely related to fibrosis development, while DTP@DMF NPs could attenuate macrophage activity and fibrosis in mice. RAW264.7 and NIH-3T3 cells coculture revealed that DTP@DMF NPs could promote Nrf2 and downstream heme oxygenase-1 (HO-1) expression and suppress TGF-ß and ROS production in macrophages, thereby reducing fibroblast-to-myofibroblast transition and collagen production by NIH-3T3 cells. In vivo experiments confirmed the above findings. Compared with direct DMF instillation, DTP@DMF NPs treatment presented enhanced antifibrotic effect. DTP@DMF NPs also had a prolonged residence time in the lung as well as excellent biocompatibility. CONCLUSIONS: DTP@DMF NPs can reduce macrophage-mediated fibroblast-to-myofibroblast transition and extracellular matrix deposition to attenuate lung fibrosis by upregulating Nrf2 signaling. This ROS-responsive liposome is clinically promising as an ideal delivery system for inhaled drug delivery.

A novel combined therapeutic strategy of Nano-EN-IR@Lip mediated photothermal therapy and stem cell inhibition for gastric cancer.

Recurrence and metastasis of gastric cancer is a major therapeutic challenge for treatment. The presence of cancer stem cells (CSCs) is a major obstacle to the success of current cancer therapy, often leading to treatment resistance and tumor recurrence and metastasis. Therefore, it is important to develop effective strategies to eradicate CSCs. In this study, we developed a combined therapeutic strategy of photothermal therapy (PTT) and gastric cancer stem cells (GCSCs) inhibition by successfully synthesizing nanoliposomes loaded with IR780 (photosensitizer) and EN4 (c-Myc inhibitor). The nanocomposites are biocompatible and exhibit superior photoacoustic (PA) imaging properties. Under laser irradiation, IR780-mediated PTT effectively and rapidly killed tumor cells, while EN4 synergistically inhibited the self-renewal and stemness of GCSCs by suppressing the expression and activity of the pluripotent transcription factor c-Myc, preventing the tumor progression of gastric cancer. This Nano-EN-IR@Lip is expected to be a novel clinical nanomedicine for the integration of gastric cancer diagnosis, treatment and prevention.

Curc-mPEG454, a PEGylated Curcumin Derivative, Improves Anti-inflammatory and Antioxidant Activities: a Comparative Study.

We previously demonstrated that a PEGylated curcumin (Curc-mPEG454) significantly inhibited cyclooxygenase 2 (COX-2) expression and improved the progression of liver fibrosis. The current study systematically evaluates its anti-inflammatory and antioxidant activities in vitro in a comparative study with curcumin, aspirin, NS-398, and vitamin C. RAW264.7 murine macrophages were pretreated with Curc-mPEG454, curcumin, aspirin, NS-398, or vitamin C at the indicated concentration for 2 h; then, the cells were stimulated with 1 µg/mL lipopolysaccharide (LPS) for 24 h. The levels of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, PGE2, NO, and GSH, and the activities of COX-2, SOD, and CAT, and the transcription factors involved in inflammation, such as NF-κB, c-Jun, and Nrf2, were measured. Curc-mPEG454 showed lower cytotoxicity (IC50 57.8 µM) when compared with that of curcumin (IC50 32.6 µM) and inhibited the release of the inflammatory cytokines IL-6, TNF-α, IL-1ß, and MCP-1 in a concentration-dependent manner. At 16 µM, Curc-mPEG454 was most potent in the suppression of COX-2 expression at a transcriptional level rather than in the suppression of the catalytic activity of COX-2. Like curcumin, Curc-mPEG454 significantly reduced intracellular ROS production and enhanced the activities of SOD and CAT and the level of GSH to protect cells from LPS-induced oxidative injury. Further, its anti-inflammatory and antioxidation mechanisms are related to inhibition of NF-κB p65 nuclear translocation and c-Jun phosphorylation and to activation of Nrf2. Taken together, these findings indicate that PEGylation of curcumin not only improves its biological properties but also interferes with multiple targets involved in the inflammatory response. Curc-mPEG454 is a powerful and beneficial anti-inflammatory and antioxidant agent that merits further investigation. Graphical Abstract ᅟ.